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Hunter Lee
Hunter Lee

The Term E6 ((NEW))

The carboxy terminal 350 amino acids form the conserved hect domain of E6-AP, a region of homology shared by several proteins structurally and functionally related to E6-AP [Huibregtse et al., 1995]. The hect domain of E6-AP has a 40 kDa conserved carboxy-terminal catalytic domain that has at least four biochemical functions: 1) it binds to specific E2 ubiquitin-conjugating enzymes like UbcH7, UbcH5B and UbcH8; 2) it accepts ubiquitin from E2 enzyme, forming a ubiquitin-thioester intermediate with its active site cysteine [Kumar et al., 1997]. A conserved cysteine residue at position 833 in the hect domain confers the ubiquitin ligase activity of E6-AP. In vitro studies have shown that the mutation of cysteine 833 residue to alanine or serine renders it unable to form a thioester bond with ubiquitin; 3) it transfers ubiquitin to the ε-amino groups of lysine side chain on the substrate by catalyzing the formation of an isopeptide bond; and 4) it transfers additional ubiquitin molecules to the growing end of the multi-ubiquitin chain [Huang et al., 1999; Scheffner et al., 1995].

the term e6

E6-AP has been shown to function as an E3 ligase in the ubiquitination of p53 in cooperation with HPV E6 protein [Cooper et al., 2003]. The viral E6 protein acts as an adaptor between p53 and E6-AP [Huibregtse et al., 1993]. This E6-dependent binding of p53 to E6-AP involves amino acids 280-781 of E6-AP, which form the central leucine-rich core that is crucial for the biological function and structural stability of E6-AP. An 18 amino acid region of E6-AP, from 391-408, has been shown to be necessary and sufficient for binding to E6 [Zanier et al., 2005]. This sequence was later characterized as a leucine-rich peptide, LQELL, which is a signature LXXLL motif (a receptor interacting motif) [Cooper et al., 2003; Kishino et al., 1997; Scheffner et al., 1993; Talis et al., 1998]. An essential intermediate step in E6-AP-dependent ubiquitination is the formation of a thioester complex between E6-AP and ubiquitin-conjugating enzymes. In the case of ubiquitin-conjugating enzyme UbcH5B, the implicated binding site corresponding to amino acids 521-679 of E6-AP, falls within the central leucine-rich core of E6-AP (Figure 2). The region of E6-AP involved in complex formation with UbcH7 and UbcH8 was mapped to its hect domain [Huang et al., 1999; Scheffner et al., 1994]. Recently, Mani et al. identified AIB1 (amplified in breast cancer 1)/SRC-3 (steroid receptor coactivator-3) as a substrate for E6-AP-mediated ubiquitination and established that the steady-state level of AIB1 is regulated by E6-AP. The interaction between E6-AP and AIB1 is mediated through the carboxy terminus of AIB1 [Mani et al., 2006].

E6-AP possesses five well-characterized functional domains: (i) a hect domain, (ii) an E6 binding domain, (iii) a p53 binding domain, (iv) two nuclear receptor interaction domains and (v) an activation domain, which have been represented with the amino acid numbers they correspond to. The three LXXLL motifs (NR box) are shown dispersed throughout the protein. Two of these motifs are located in the amino terminus and the third one is located within the carboxy terminus of the protein.

The characterization of E6-AP as a coactivator for SHRs, along with the observations that several nuclear receptors are ubiquitinated and degraded in the course of their transcriptional activities, suggests that ubiquitin proteasome-mediated protein degradation plays a crucial role in eukaryotic transcription (Figure 3) [Alarid, 2006; Ismail and Nawaz, 2005]. The evidence implicating the 26S proteasome in the control of nuclear receptor stability was provided by proteasome inhibition studies using MG132, lactacystin, and other proteasome inhibitors. Proteasome inhibition significantly diminished the ligand-induced transcriptional activity of most of the NRs, which includes AR, ER, PR, RAR-α, TR, peroxisome proliferator-activated receptor (PPAR) and retinoid X receptor (RXR) [Alarid, 2006; Ismail and Nawaz, 2005; Lonard et al., 2000; Nawaz et al., 1999a]. Because of the broad cellular effects of proteasome inhibitors, it is difficult to directly link their functional outcome to the stability of the receptor alone. Thus, considerable effort is being focused on determining the specific E3 ligases involved in targeting the receptors for proteolysis. Although the identity of the E3 ligase(s) involved in ER-α proteolysis has remained controversial and elusive, there is evidence correlating ER-α and AR protein stability to the level of E6-AP expression [Gao et al., 2005; Khan et al., 2006]. The interaction of E6-AP with the ER-α and AR and its recruitment to their target gene promoters supports the idea that E6-AP might be one of the E3 ligases responsible for the ubiquitination and degradation of ER-α and AR [Dhananjayan et al., 2006; Khan et al., 2006; Reid et al., 2003]. This notion was confirmed in the prostate glands of E6-AP null mice, where, although the level of AR protein was elevated, the level of an AR target protein, Probasin, was decreased. Despite the identification of E6-AP as a modulator of receptor transcription function, its activity in relation to ubiquitination and proteolysis of receptors is yet to be determined.

Four ng of [α-32P] rCTP-labeled pre-mRNA transcribed in vitro was mixed with 8 µl (7.5 µg/µl) of HeLa nuclear extract in a reaction volume of 20 µl in the presence of the reaction buffer containing final concentration of 40% HeLa nuclear extract, 5.0 mM HEPES (pH 7.9), 0.6% polyvinyl alcohol, 0.4 mM ATP, 20 mM creatine phosphate, 3 mM MgCl2. After incubation at 30C for 30 min, the mixture was incubated for additional 10 min at 30C in the presence of 500 nM DNA oligo oMA64 for wild type BPS, oMA76 for mt-11 BPS, oMA60 for mt-7 BPS, or oMA61 (Table S2) for PPT, depending on which 32P-labeled pre-mRNA was used. Subsequently, the reaction was digested at 30C for 10 min, terminated by addition of 60 µl of proteinase K solution (5 mg/ml proteinase K [Roche Diagnostics], 50 mM EDTA, 0.5% [W/V] SDS) and incubated for 20 min at 75C. The digested products were extracted by phenol/chloroform/isoamyl alcohol and were resolved in a 6% denaturing PAGE gel containing 7.5 M Urea (National Diagnostics). The PAGE gel was then transferred onto a 3M filter paper and dried. The radioactivity of the digested products was captured by exposing the filter paper to a storage phosphor screen (Molecular Dynamics). The screen was then imaged by a PhosphoImager STORM 860 and analyzed with ImageQuant software (Molecular Dynamics).

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Its scope is unique. The term "oncotarget" encompasses all molecules, pathways, cellular functions, cell types, and even tissues that can be viewed as targets relevant to cancer as well as other diseases. The term was introduced in the inaugural Editorial, Introducing OncoTarget. 041b061a72


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